Stroke is the third leading cause of death in the United States and the leading cause of disability. Diseases of neurodegeneration and brain damage from non-missile head trauma account for nearly 500,000 hospital admissions in the U.S. annually. Although the etiology may differ, the same anatomic and physiologic substrates are involved in these conditions, including ischemia and hypoxic injury and the release of excitatory amino acids, especially glutamate from diseased or damaged cells. We have been using in vitro and in vivo models of experimental ischemia and cellular models of glutamate toxicity to examine these mechanisms of neuronal injury, and to target early intervention treatment strategies for neurodegeneration. One promising strategy that has not been explored is the use of low doses of chemicals to enhance cell tolerance and recovery. High doses of toxic chemicals will inhibit and kill biological systems, while low doses frequently stimulate those systems. Stimulation of cell function by exposure to low doses of chemicals can often mitigate the adverse effects produced by high doses. This phenomenon has been extensively studied in the area of toxicology called "hormesis" and is the theoretical basis for the observed effects in some types of homeopathy (specifically isopathy). While paradoxical dose effects have been demonstrated across multiple cell types and phyla they have not yet been examined in neurodegeneration. In preliminary research we have demonstrated that protective effects occur in neuronal cells exposed to low and ultra-low doses of glutamate and NMDA and that certain doses of glutamate/potassium combinations protect against stroke in vivo. The objective of this project is to use neuronal culture systems to identify the optimal protective doses and of four neurotoxins that work by different mechanisms - a glutamate/potassium preparation, NMDA, cycloheximide, MPPepsilon, a combination of these. We will also begin preliminary examination of selected mechanisms of the optimal protective combination and dose. This project will, for the first time, have produced a systematic approach for use of protective hormesis and will lay the foundation for the scientific development of homeopathic and isopathic drugs in neurodegeneration and brain injury.